PROJECT SUMMARY Alzheimer?s Disease (AD) is a major aging-related neurological disorder that afflicts roughly 5.3 million Americans, with total US annual costs of ~ $226 billion. Despite intensive efforts to characterize the regulation of pathological processes of AD, particularly the generation of ?-amyloid plaques, current interventions aimed at blocking ?-amyloid aggregation have only modest effects on clinical symptoms, suggesting that new approaches to find risk factors independent of ?-amyloid aggregation should be investigated, particularly to identify proximal causes of the disease. Genetic studies in model organisms have demonstrated that evolutionarily conserved pathways modulate aging, and interventions that target these pathways can dramatically extend mammalian healthspan and lifespan. C. elegans has been at the forefront of model organism longevity studies, revealing new genes, pathways, and molecular mechanisms that regulate the rate of aging and age-related declines, including cognitive decline. In parallel, Genome-wide association (GWAS) studies have implicated a role for gene regulatory changes as a risk factor for AD. AD risk variants in gene regulatory regions may dysregulate context-specific transcriptional outputs, contributing to susceptibility to AD independent of the regulation and generation of ?-amyloid plaques. Our hypothesis is that by defining a cell?s gene regulatory networks during aging and in genetically predisposed AD neuropathological states, it will be possible to both infer the environmental signals the cell receives and explain its resulting program of gene expression. These age- dependent transcriptional changes may be conserved in neurons across evolutionary time scales, and may contribute to cognitive decline in the model system C. elegans, as well. We will leverage the strengths of this model system (simple genetics, short lifespan, rapid aging, functional assays of learning and memory, and transcriptional analysis of isolated neurons), combined with data from genomic and genetic studies of AD and experimental results from human neuronal cells, to identify shared gene regulatory networks that may contribute to the susceptibility to AD. These genes and gene networks will provide important new targets for pharmaceutical interventions for the onset and progression of Alzheimer?s Disease.